title: The level of H₂O₂ type oxidative stress regulates virulence of Theileria-transformed leukocytes.
abstract: Theileria annulata infects predominantly macrophages, and to a lesser extent B cells, and causes a widespread disease of cattle called tropical theileriosis. Disease-causing infected macrophages are aggressively invasive, but this virulence trait can be attenuated by long-term culture. Attenuated macrophages are used as live vaccines against tropical theileriosis and via their characterization one gains insights into what host cell trait is altered concomitant with loss of virulence. We established that sporozoite infection of monocytes rapidly induces hif1-α transcription and that constitutive induction of HIF-1α in transformed leukocytes is parasite-dependent. In both infected macrophages and B cells induction of HIF-1α activates transcription of its target genes that drive host cells to perform Warburg-like glycolysis. We propose that Theileria-infected leukocytes maintain a HIF-1α-driven transcriptional programme typical of Warburg glycolysis in order to reduce as much as possible host cell H2 O2 type oxidative stress. However, in attenuated macrophages H2O2 production increases and HIF-1α levels consequently remained high, even though adhesion and aggressive invasiveness diminished. This indicates that Theileria infection generates a host leukocytes hypoxic response that if not properly controlled leads to loss of virulence.
authors.affiliation: Laboratoire de Biologie Cellulaire Comparative des Apicomplexes, Faculté de Médicine, Université Paris Descartes - Sorbonne Paris Cité, Paris, France; Inserm U1016, Cnrs UMR8104, Cochin Institute, Paris, 75014, France.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Metheni
authors.forename: Nadia
authors.initials: N
authors.lastname: Echebli
authors.forename: Marie
authors.initials: M
authors.lastname: Chaussepied
authors.forename: Céline
authors.initials: C
authors.lastname: Ransy
authors.forename: Christiane
authors.initials: C
authors.lastname: Chéreau
authors.forename: Kirsty
authors.initials: K
authors.lastname: Jensen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Glass
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bouillaud
authors.forename: Gordon
authors.initials: G
authors.lastname: Langsley
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D006019:Glycolysis; D006861:Hydrogen Peroxide / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology*; D018384:Oxidative Stress; D016796:Theileria annulata / Q000276:immunology*
chemical_list: D006861:Hydrogen Peroxide